MultiOmic characteriZation of Acute Myeloid Leukemia Evolving From myelopRoliferative Neoplasm to Identify New Targeted Therapeutic Strategies

NCT06022341 | Not Yet Recruiting

• 1 other identifier: 49RC23_0288.
• Study Type: interventional
• Target: 120
• Locations: 0 countries
• Sites: N/A

Brief Summary

Myeloproliferative neoplasms (MPN) are chronic myeloid malignancies characterized by a risk of evolution to acute myeloid leukemia (AML). This unpredictable complication is associated with a grim outcome with median overall survival ranging between 2 to 10 months. To date, even allogeneic transplantation fails to significantly improve the prognosis. Biological and molecular mechanisms driving leukemic transformation are complex, ill-defined, and heterogeneous between patients. The investigator hypothesize that deciphering the molecular heterogeneity of post-MPN AML may lead identifying efficient drugs targeting of the most relevant leukemogenic pathways. Our main objective is to identify new targeted therapeutic approaches in post-MPN AML through in-depth characterization of the dysregulated pathways. The investigator will first characterize in an already annotated cohort of 120 post-MPN AML homogeneous patients subgroups using comprehensive multiomic analyses. Dysregulated pathways will be identified in each subgroup using the omics data and single-cell RNA-sequencing will be performed in a subset of patients in each subgroup. A customised drug-panel will be derived from the dysregulated pathway for an ex vivo drug screening, which will use a flow-cytometry read-out enabling to identity drug effect on cells survival, differentiation, and stemness. The 3 most promising drugs will be validated in a preclinical in vivo model of patient's derived xenograft (PDX) and their impact on clonal architecture will be studied in primary cell cultures using single-cell DNA-sequencing. Overall, this proposal may provide a better understanding of MPN leukemic transformation mechanisms and provide a path for personalized therapies. Our findings may therefore pave the way to drugs development in post-MPN AML that would provide a rationale for implementation of early clinical trials in these dreadful diseases.

Conditions

Myeloproliferative Neoplasm; Secondary Leukemia

Keywords

multiomics; in vitro drug screening

Outcome Measures

Primary Outcomes (1)

• Ward's minimum variance criterion to minimize the intra-cluster variance

  Decipher the heterogeneity of post-MPN AML to identify homogeneous subgroups

  24 months

Secondary Outcomes (5)

• GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways identified among the different subgroups by integration of omics data, cell type and trajectories inferred using scRNA-Seq

  36 months

• Median effective concentration (EC50) of each evaluated drug

  36 months

• Mice survival

  48 months

• Leukemic disease burden modification

  48 months

• Identify the effect of the best candidate drugs/therapeutic combinations at the single-cell level and assess how clonal architecture evolves after treatment

  48 months

Study Arms (1)

Leukemic transformation of myeloproliferative neoplasms

OTHER

120 patients will be studied for : * Multiomic characterization * In vitro drug screening

Other: Multiomic characterization; Other: In vitro drug screening

Interventions

Multiomic characterization OTHER

Multiomics analysis include targeted-NGS with a 400-genes panel, RNA-seq and methylome. All the genomic libraries will be constructed at the genomic facility of Angers University Hospital and the sequencing will be performed on a NovaSeq6000 in the GenoBIRD Platform in Nantes. Bioinformatic analysis will be performed and will derive for each sample: SNV/Indel and CNV from DNA sequencing, expression of mRNA and lncRNA, genes fusion and splicing events from RNA-seq, and methylation beta-values from methylome.

Leukemic transformation of myeloproliferative neoplasms

In vitro drug screening OTHER

The drug screening will be performed on the 'NEXT-AML' platform at St-Louis Hospital, Paris. This platform uses a multiparametric screening strategy based on flow cytometry measurements of cell viability, cell differentiation and stem cell compartment. Primary patient cells will be cultured in a specific niche-like medium with amino-acids, cytokines and stromal cells (Dal Bello et al. 2022). Twenty-five drugs at 6 concentrations covering a 1000-fold concentration range will be studied for each sample.

Leukemic transformation of myeloproliferative neoplasms

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with a prior diagnosis of MPN: polycythemia vera, essential thrombocythemia or primary myelofibrosis according to the WHO criteria
• Acute myeloid leukemia evolution defined by ≥ 20% of blasts cells
• Available material from bone marrow sampling at the time of leukemic transformation (i.e. ≥ 20% of blasts cells): DNA (1µg), RNA (500ng) +/- frozen mononuclear cells in DMSO for a subset of 60 patients (2 vials of at least 8 millions cells).
• Informed consent (or requalification procedure)

You may not qualify if:

• \- Patient not affiliated to the French health insurance

Sponsors & Collaborators

• University Hospital, Angers: lead
• University Hospital, Brest: collaborator
• Institut Paoli-Calmettes: collaborator
• Saint-Louis Hospital, Paris, France: collaborator
• Gustave Roussy, Cancer Campus, Grand Paris: collaborator

MeSH Terms

Conditions

Myeloproliferative Disorders

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases

Study Officials

• Damien LUQUE PAZ, PharmD. PhD.

  University Hospital of Angers

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Damien LUQUE PAZ, PharmD. PhD.

CONTACT

241355353; damien.luquepaz@chu-angers.fr

Béatrice GABLE

CONTACT

241356825; begable@chu-angers.fr

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Masking Details: Patients will be recruited in the French biobank of MPN (BCB INCa FIMBANK) and the FILO's national biobank of acute leukemias (FILOthèque). All clinical and biological data are anonymized.
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 22, 2023
• First Posted: September 1, 2023
• Study Start: October 15, 2023
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2028
• Last Updated: September 1, 2023

Record last verified: 2023-08

Data Sharing

• IPD Sharing: Will not share